Targeting gasdermin E in neurodegenerative diseases
Authors: Zhi Dong Zhou, Ling Xiao Yi, Eng King Tan
Journal: Cell Reports Medicine (2023)

Neel et al. identified pathophysiologic clues linking gasdermin-E (GSDME) with frontotemporal dementia and amyotrophic lateral sclerosis.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Therapeutic studies targeting GSDME may provide a viable approach for neurodegenerative diseases. Neel et al. identified pathophysiologic clues linking gasdermin-E (GSDME) with frontotemporal dementia and amyotrophic lateral sclerosis.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Therapeutic studies targeting GSDME may provide a viable approach for neurodegenerative diseases. The gasdermin E (GSDME) protein is a tumor suppressor involved in pyroptosis, a form of lytic and proinflammatory programmed cell death.2Xia S. Hollingsworth 4th, L.R. Wu H. Mechanism and regulation of Gasdermin-mediated cell death.Cold Spring Harb. Perspect. Biol. 2020; 12a036400https://doi.org/10.1101/cshperspect.a036400Crossref Scopus (70) Google Scholar The GSDME protein contains a cytotoxic N-terminal domain (GSDME-N), an auto-inhibitory C-terminal domain (GSDME-C), and an interdomain linker (Figure 1). Under physiological conditions, GSDME-N domain binds to the hydrophobic core of the inhibitory GSDME-C domain via electrostatic and hydrophobic interactions to suppress GSDME-N toxicity.3Li Y.Q. Peng J.J. Peng J. Luo X.J. The deafness gene GSDME: its involvement in cell apoptosis, secondary necrosis, and cancers.Naunyn-Schmiedeberg's Arch. Pharmacol. 2019; 392: 1043-1048https://doi.org/10.1007/s00210-019-01674-7Crossref Scopus (15) Google Scholar However, stress-activated caspases cleave the GSDME protein at its interdomain linker, leading to dissociation of GSDME-N and GSDME-C (Figure 1).3Li Y.Q. Peng J.J. Peng J. Luo X.J. The deafness gene GSDME: its involvement in cell apoptosis, secondary necrosis, and cancers.Naunyn-Schmiedeberg's Arch. Pharmacol. 2019; 392: 1043-1048https://doi.org/10.1007/s00210-019-01674-7Crossref Scopus (15) Google Scholar The released GSDME-N fragment oligomerizes and forms large pore structures in plasma and mitochondrial membranes, leading to the release of inflammatory components and mitochondrial cytochrome c, resulting in programmed lytic cell death.4Rogers C. Alnemri E.S. Gasdermins: novel mitochondrial pore-forming proteins.Mol. Cell. Oncol. 2019; 6e1621501https://doi.org/10.1080/23723556.2019.1621501Crossref Scopus (18) Google Scholar In a recent study, Neel et al. highlighted that GSDME has higher expression in both mouse and human neurons compared to glia.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Treatment of primary mouse cortical neurons and human SH-5YSY cells with Rotenone and 6-hydroxyldopamine (mitochondrial toxins) led to activation of caspase 3, resulting in GSDME cleavage and releasing toxic GSDME-N in a caspase-dependent manner. These actions contributed to mitochondrial localization of GSDME-N, distal axon mitochondria depolarization, and neurite retraction.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Transfection and expression of GSDME-N in primary mouse neurons without mitochondrial toxin challenges led to GSDME-N mitochondrial localization in cell bodies and axons, followed by the loss of mitochondrial membrane potential and neurite retraction.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Overexpression of the transactivation-responsive region (TAR) DNA binding protein-43 and C9ORF72 hexanucleotide expansion-associated dipeptide repeat protein PR-50, two frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated proteins, promoted GSDME-dependent mitochondria damage and neurite loss.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar However, Rotenone-induced SH-SY5Y cell demise can be rescued by GSDME gene knockout (KO).1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar GSDME KO can also inhibit neuroinflammation, abrogate neuron loss and alleviate motor dysfunction symptoms in an SOD1G93A ALS mice model.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Furthermore, knockdown of GSDME can protect against neurite loss and neurodegeneration in induced pluripotent stem cell-derived motor neurons from ALS patients.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar These findings suggest GSDME as a common pathway executioner of mitochondrial dysfunction and a potential therapeutic target for human neurodegenerative diseases. While the pathophysiological roles of GSDME in the nervous system have not been fully elucidated, therapeutic strategies to target GSDME should be further explored. First, the neurotoxicity of activated GSDME can potentially be ameliorated by blood-brain-barrier (BBB)-penetrable neutralizing antibodies or functional antibody fragments (Figure 1a). The therapeutic effects of BBB-penetrating neutralizing antibodies for neurodegenerative diseases have been previously demonstrated, including the bispecific antibody protocol targeting both protein targets and insulin receptor or transferrin receptor 1 (TfR1) to enhance antibody BBB penetration through insulin and TfR1 receptor mediated transcytosis.5Sehlin D. Fang X.T. Meier S.R. Jansson M. Syvänen S. Pharmacokinetics, biodistribution and brain retention of a bispecific antibody-based PET radioligand for imaging of amyloid-β.Sci. Rep. 2017; 717254https://doi.org/10.1038/s41598-017-17358-2Crossref Scopus (33) Google Scholar Second, the oligomerization and membrane insertion of GSDME-N can be explored using small molecular compounds, drugs, or interacting peptides (Figure 1b). Investigators have used this approach, demonstrating that polyphenol compounds were able to inhibit α-syn oligomer formation and disaggregate preformed α-syn oligomeric structures.6Caruana M. Högen T. Levin J. Hillmer A. Giese A. Vassallo N. Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds.FEBS Lett. 2011; 585: 1113-1120https://doi.org/10.1016/j.febslet.2011.03.046Crossref PubMed Scopus (224) Google Scholar Third, interaction peptides combined with arginine-arginine-arginine-glycine (RRRG) proteasome degradation signal (PDS) may be able to facilitate GSDME-N proteasome degradation and promote neuron survival (Figure 1c). The peptide from β-synuclein (β-syn) protein plus C-terminal RRRG PDS can bind with α-syn and induce α-syn protein proteasome degradation in Parkinson's disease models.7Jin J.W. Fan X. del Cid-Pellitero E. Liu X.-X. Zhou L. Dai C. Gibbs E. He W. Li H. Wu X. et al.Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.Commun. Biol. 2021; 4: 232https://doi.org/10.1038/s42003-021-01746-6Crossref PubMed Scopus (8) Google Scholar Peptide screening studies can potentially identify GSDME-N binding peptides from peptide libraries, endogenous GSDME-N binding proteins, GSDEM-N fragments for self-oligomerization, or the hydrophobic core of GSDME-C to interact with GSDME-N. After identification of GSDME-N binding peptides, RRRG PDS can be added to promote proteasome degradation and inhibit GSDME-N toxicity in neurons. Fourth, the GSDME-N toxicity can be modulated by protein kinase-induced phosphorylation (Figure 1d). The kinase-induced phosphorylation of highly conserved threonine (Thr) 6 residue of GSDME-N can inhibit its membrane pore-forming activity via disturbance of GSDME-N oligomerization.8Rogers C. Erkes D.A. Nardone A. Aplin A.E. Fernandes-Alnemri T. Alnemri E.S. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation.Nat. Commun. 2019; 10: 1689https://doi.org/10.1038/s41467-019-09397-2Crossref PubMed Scopus (359) Google Scholar Elucidating the functions of up-stream protein kinases of GSDME-N and efforts to modulate GSDME-N phosphorylation may uncover new, exciting therapeutic clues. In summary, Neel et al. highlighted that an activated GSDME can promote neurodegeneration in ALS and FTD models.1Neel D.V. Basu H. Gunner G. Bergstresser M.D. Giadone R.M. Chung H. Miao R. Chou V. Brody E. Jiang X. et al.Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.Neuron. 2023; 111: 1222-1240.e9https://doi.org/10.1016/j.neuron.2023.02.019Abstract Full Text Full Text PDF Scopus (0) Google Scholar Different therapeutic strategies targeting GSDME should be further explored. Longitudinal clinical studies to monitor GSDME-N and GSDME-C levels in ALS and FTD patients to determine their suitability as disease biomarkers may be useful. We thank National Medical Research Council (CS-IRG, HLCA, PD OF LCG 000207, and STaR) and DUKE-NUS Medical School for their support. The authors declare no competing interests.